3,4,5,6,7,8-hexahydro-2(1h)-naphthalenones



United States Patent 3,497,557 3,4,5,6,7,8-HEXAHYDRO-2(1H)-NAPHTHALENONES Daniel Lednicer, Portage, Mich., assignor to The UpjohnCompany, Kalamazoo, Mich., a corporation of Delaware No Drawing.Continuation-impart of application Ser. No. 364,288, May 1, 1964. Thisapplication Nov. 13, 1967, Ser. No. 682,633

Int. Cl. C07c 49/44 US. Cl. 260590 2 Claims ABSTRACT OF THE DISCLOSUREThe invention is a group of organic compounds having the followingformula:

where R, is hydrogen, alkyl, or halogen, and R is hydrogen, lower-alkyland halogen. These compounds are useful as antifertility agents.

wherein R is selected from the class consisting of hydrogen, andlower-alkyl and halogen; and wherein R is selected from thelower-alkoxy, lower-alkoxy substituted by "ice a group selected from theclass consisting of (a) dihydroxyalkyl from 2 to 5 carbon atoms,inclusive, (b) 2- amino 1 hydroxyethyl, (c) 5 (2-thioxo-oxazolidinyl)-,(d(; 51- (2 oxooxazolidinyl)-, and (e) epoxyethyl, the ra ica whereinC,,H is alkylene from 2 to 6 carbon atoms, inclusive, R and R takenindividually represent loweralkyl, and R and R taken together with theattached nitrogen atom represent the residue of a saturated heterocyclicradical of from 5 to 7 atoms, inclusive, and the radical -OC H -Rwherein C H is alkylene from 1 to 12 carbon atoms, inclusive, and R isselected from the class consisting of carboxy and lower-carbalkoxy.

The term lower-alkyl means an alkyl radical of from 1 to 8 carbon atoms,inclusive, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, and isomeric forms thereof. The term halogen means fluorine,chlorine, bromine, and iodine. The term lower-alkoxy means alkoxycontaining from 1 to 8 carbon atoms, inclusive, such as methoxy, ethoxy,propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, and isomericforms thereof. The term alkylene from 2 to 6 carbon atoms, inclusivemeans ethylene, propylene, butylene, pentylene, hexylene, and isomericforms thereof.

The novel compounds of the invention as defined above possesspharmacological activity. lllust-ratively, the compound 3,4,5,6,7,8hexahydro-5,6-diphenyl-2(1H)-naphthalenone exhibits oral antifertilityactivity in rats when tested by the method described by Duncan et al.,Proc. Soc. Exp. Biol. Med. 112, 439442, 1963.

The novel compounds of the invention are valuable for animal pestcontrol. For example, the compounds 0;. the invention are formulated incombination with baits and/or att-ractants and placed in feedingstations accessible to undesirable rodents and other small animalsineluding Canidae such as coyotes, foxes, wolves, jackals, and wild dogsand birds such as starlings, gulls, redwing blackbirds, pigeons, and thelike, thus reducing hazards to aviation by their presence on runways andin the vicinity of airfields, the spread of disease, and destruction toproperty in both rural and urban areas.

For purposes of administration to birds and to mammals, includinganimals of economic value such as horses, cattle, sheep, pigs, mice,rats, rabbits, and the like, the novel compounds of the invention can becombined with solid or liquid pharmaceutical carriers and formulated inthe form of tablets, powder packets, capsules, and like solid dosageforms, using starch and like excipients, or dissolved or suspended insuitable solvents or vehicles, for oral or parenteral administration.

The novel compounds of the invention are prepared in accordance with thereactions shown in the following flow-sheet:

which this reaction is carried out, which procedure is employed in thecontext of the present invention, has been extensively reviewed in theliterature; see, for example,

(III) wherein R and R are as defined above.

The l,2-diphenyl-6-alkoxy-3,4-dihydronaphthalenes (I) employed asstarting materials are subjected to reduction by methods Well known inthe art for the saturation of ethenoid bonds to give the corresponding1,2,3,4-tetrahydronaphthalenes (II). The reduction can be effected usingreducing agents such as sodium in the presence of an alkanol, forexample, methanol, ethanol, propanol, isobutyl alcohol, and the like,and lithium and like alkali metals in the presence of liquid ammonia.The use of lithium and liquid ammonia is the preferred method ofeffecting the reduction of (I) to (II).

Using the latter reducing agent, the reduction can be carried out byadding an approximately stoichiometric amount of lithium, advantageouslyin the form of lithium wire, to a solution of the dihydronaphthalene (I)in a mixture of liquid ammonia and an inert organic solvent such astetrahydrofuran, benzene, toluene, ethanol, methanol, isobutyl alcohol,tertiary butyl alcohol, and the like, or a mixture of such solvents. Thereduction occurs rapidly and is usually substantially complete in aperiod of from about minutes to about 1 hour, though longer reactionperiods may be necessary with certain compounds. The desired product(II; R =X) is isolated from the reaction mixture by conventionalprocedures; for example, by evaporation of solvent after addition ofammoniurn chloride, followed by solvent extraction of the residue,evaporation of solvent from the extract, and purification of theresulting product by recrystallization, chromatography, or likeconventional procedures.

The compounds of the invention having the Formula III wherein R ishydrogen, lower-alkyl or halogen are obtained by subjecting thecorresponding compounds having the Formula II to, a Birch reduction. Thelatter reductive procedure, named after A. I Birch who was responsiblefor its discovery, involves the use of lithium in liquid ammonia as hereducing agent. The procedure under Quarterly Reviews 4, 69, 1950;ibid., 12, 17, 1958. Generally speaking, the Birch reduction is carriedout in the context of the present invention by adding metallic lithium,preferably in the form of a wire, portionwise to a solution of thecompound (II) in a mixture of liquid ammonia and a combination of inertorganic solvents one of which is an ether such as tetrahydrofuran,diethyl ether and dioxane, and the other is an alkanol such as ethanol,isopropyl alcohol, butanol, t-butyl alcohol, and the like. The lithiumis preferably employed in excess of the stoichiometric proportions,advantageously in an excess of the order of about 10 gram-atoms oflithium per mole of compound (II). When the reduction is substantiallycomplete, as determined by analytical techniques such as paper or thinlayer chromatography and the like, the mixture is treated with ammoniumchloride and the solvents are removed by evaporation. The desiredcompound (III) is isolated from the residue by conventional techniques,for example, treatment with water followed by isolation of the insolublematerial by filtration and purification by recrystallization,chromatography, and like techniques.

The compounds of the invention having the Formula IV are obtainedconveniently by acid hydrolysis of the corresponding compounds ofFormula III. The hydrolysis can be carried out in aqueous or aqueousalcoholic solutions using dilute mineral acids such as hydrochloric,hydrobromic, sulfuric, phosphoric, and the like, or preferably usingorganic acids such as oxalic acid, acetic acid, propionic acid, and thelike. The hydrolysis is carried out advantageously at or below roomtemperature (approxi mately 20 to 25 C.). The hydrolysis of the enolether group at position 6 and rearrangement with formation of theresulting 6-keto compound (IV) can be followed by analytical techniquessuch as infrared spectral analysis. When the reaction is substantiallycompleted, as shown by said analytical techniques, the desired compound(IV) is isolated from the reaction mixture by conventional techniques,for example, by neutralization followed by evaporation of the solvent.The residue is subjected to solvent extraction or like techniques toisolate the compound (IV), which latter is purified by conventionaltechniques such as recrystallization, chromatography, and the like.

The compounds of the invention having the Formula V are obtained byrearrangement of the corresponding compounds of Formula IV. Saidrearrangement is carried out by treating the compound (IV) with strongmineral acid such as concentrated hydrochloric acid, sulfuric acid,hydrobromic acid, phosphoric acid or the like, or by treatment withstrong base such as sodium hydroxide, potassium hydroxide, potassiumethoxide, sodium methoxide, and the like. The reaction is advantageouslycarried out in concentrated aqueous or alcoholic solution atapproximately the boiling point of the reaction mixture. When therearrangement is substantially complete, as determined by infrared orlike anlytical techniques, the desired compound (V) is isolated from thereaction mixture by conventional techniques such as by neutralizationfollowed by evaporation to dryness and purification of the residue byconventional techniques such as solvent extraction, countercurrentdistribution, chromatography, recrystallization, and the like, or anycombination of these techniques.

The compounds having the Formula I which are employed as startingmaterials in the process of the invention can be prepared according tothe following reaction scheme:

| CH3 R o n-o 3 i) ll (VI) (VII) R0 \ff/ (VIII) NC R1 HO O C R1 (I? RH0O C R1 R0 RO (XII) (XI) In the above formulae R and R have thesignificance hereinbefore defined.

In the above reaction sequence, the appropriately substitutedacetophenone (VI) is condensed with the appropriately substitutedbenzaldehyde (VII) to produce the corresponding chalcone (VIII) underconditions conventionally employed in the preparation of chalcones, forexample, by condensation of (VI) and (VII) in the presence of a basesuch as sodium hydroxide, potassium hydroxide, and the like, in an inertsolvent such as a mixture of water and a lower alkanol, for example,methanol, ethanol and the like. The reaction is generally conducted ator below room temperature (approximately 20 to 25 C.) with externalcooling as required. The chalcone (VIII) is isolated from the reactionmixture and purified by conventional procedures, for example, by solventextraction followed by distillation, in the case of a liquid product, orrecrystallization in the case of a solid product.

The chalcone (VIII) so obtained is then converted to the correspondingnitrile (IX) by reaction with hydrogen cyanide, for example, bytreatment with an alkali metal cyanide such as potassium cyanide, sodiumcyanide, and the like, in the presence of acetic acid and an inertsolvent such as aqueous methanol, aqueous ethanol, and the like, usingthe procedure described by Newman, I. Am. Chem. Soc. 60, 2947, 1938 forthe conversion of benzalacetophenone (chalcone) toa-phenyl-fl-benzoylpropionitrile. The desired nitrile (IX) generallyseparates from the reaction mixture as a solid and can be isolated byfiltration and purified by recrystallization.

The nitrile (IX) so obtained is hydrolyzed to the corresponding ketoacid (X) by conventional procedures for the hydrolysis of nitriles, forexample, by heating under reflux in the presence of aqueous mineral acidsuch as sulfuric acid until hydrolysis is substantially complete. Thedesired acid (X) generally separates from the reaction mixture as asolid and is isolated by filtration and purified by recrystallization orby other conventional procedures, for example, by conversion to analkali metal salt followed by acidification of the latter to regeneratethe free acid.

The keto acid (X) so obtained is then subjected to reduction to form thecorresponding acid (XI). The reduction can be effected using any of themethods cus tomarily employed for the conversion of a keto group to amethylene group. A particularly suitable reducing agent is amalgamatedzinc; for example, treatment of the keto acid (X) with amalgamated zincin the presence of a mineral acid aifords the desired acid (XI) inexcellent yield. The acid (XI) can be isolated from the reaction mixtureby conventional procedures, for example, by decantation of the liquidreaction mixture, followed by solvent extraction of the decanted liquidand evaporation of the solvent. Generally speaking, the acid (XI) soobtained is sufiiciently pure to be used in the next step of thesynthesis without further treatment. If desired, however, the acid (XI)so obtained can be purified by conventional procedures, for example, bydistillation in the case of a liquid or recrystallization in the case ofa solid, or by conversion to an .alkali metal salt followed byacidification of the latter to yield the free acid.

In the next stage of the synthesis the acid (XI) is cyclized to therequired a-tetralone (XII) in the presence of a Lewis acid using thegeneral procedure described by Fieser and Hershberg, J. Am. Chem. Soc.61, 1272, 1939. The term Lewis acid is Well known in the art and isdefined succinctly by Fieser and Fieser, Organic Chemistry, ThirdEdition, page 138 (Reinhold, 1956). Examples of such compounds arehydrogen fluoride, boron trifluoride, arsenic trifluoride, phosphoruspentafiuoride, titanium tetrafiuoride, concentrated sulfuric acid,polyphosphoric acid, and the like. The preferred Lewis acid for use inthe above process is hydrogen fluoride.

A particularly convenient method of cyclizing the acid (XI) according tothe above procedure comprises adding the acid (XI) to liquid hydrogenfluoride with stirring and then allowing the hydrogen fluoride toevaporate at about 20 to 30 C. The desired a-tetralone (XII) is thenisloated from the residue by conventional methods, for example, bydissolving the residue in a suitable solvent such as diethyl ether,Washing the solution so obtained with an aqueous solution of a base suchas sodium carbonate, sodium hydroxide, and the like, and thenevaporating the washed solution to dryness. The a-tetralone (XII) soobtained can be purified, if desired, by conventional procedures, forexample, by recrystallization.

Alternatively, the acid (XI) can be cyclized to the a-tetralone (XII) byconversion of the acid (XI) to the corresponding acid chloride andtreatment of the latter with aluminum chloride or stannic chlorideaccording to the procedure described by Fieser et al., J. Am. Chem. Soc.60, 170, 1938.

The a-tetralone (XII) is condensed with the appropriate Grignard reagentwherein X is as hereinbefore defined with the exception noted below, andHal represents halogen, preferably bromine or iodine, to give thecorresponding compound (I). The reaction is carried out under conditionsnormally employed in conducting Grignard reactions. Thus, the reactionis carried out under anhydrous conditions, advantageously in thepresence of an inert solvent such as dibutyl ether, diisopropyl ether,tetrahydrofuran, and the like. The preferred solvent is tetrahydrofuran.The reaction can be carried out at temperatures within the range ofabout C. to about the boiling point of the solvent employed, andpreferably is carried out within the range of about to about 30 C.

The desired product (I) can be isolated from the reaction mixture byconventional procedures. For example, the reaction mixture from theabove-described Grignard reaction is decomposed by the addition ofwater, ammonium chloride, and the like, followed by separation of theorganic layer and removal of the solvent therefrom. The residue ispurified, if desired, by conventional procedures, for example, bychromatography, recrystallization, and the like.

In preparing the compounds (I) wherein X represents hydroxy from thecorresponding u-tetralone (XII) it is necessary to employ a Grignardreagent in which the group X represents a protected hydroxy group fromwhich the free hydroxy can be regenerated subsequently. A convenientmanner in which this preparation can be effected is to employ a Grignardreagent formed from the tetrahydropyranyl ether of the appropriatehalophe- 1101. The reaction of such a Grignard reagent with thea-tetralone (XII) gives rise to the desired compound (I) wherein thehydroxy group is still protected as the tetrahydropyranyl ether. Theether grouping is readily removed by Inineral acid hydrolysis and wherethe working up procedure from the Grignard reaction employs the use ofmineral acid, said ether is often removed during the working up withoutthe need to introduce a separate hydrolysis step.

The Grignard reagents employed in the conversion of the u-tetralones(XII) to the compounds (I) are prepared by reaction of magnesium in ananhydrous inert organic solvent such as dibutyl ether, diisopropylether, tetrahydrofuran, and the like, with the appropriately substitutedhalobenzene, using procedures well known in the art for the preparationof Grignard reagents.

The acetophenones (VI) which are employed as starting materials in theabove-described synthesis of the OL- tetralones (XII) can be preparedfrom the corresponding nuclear-substituted benzoic acids by convensionof the latter to the acid chlorides followed by reaction of the latterwith dimethyl cadmium according to the procedure described in ChemicalReviews 40, 15, 1947. Many of the acetophenones (VI) are known in theliterature.

The benzaldehydes (VII) which are employed as start ing materials in theabove-described synthesis of the octetralones (XII) can be obtained byreduction of the corresponding substituted benzoyl chlorides usinglithium tri-t-butoxyaluminum hydride using the procedure described byBrown et al., J. Am. Chem. Soc. 80, 5377, 1958. Many of thebenzaldehydes of the Formula VII are known in the literature.

An alternative method for the preparation of the atetralones of FormulaXII is that described by Newman, I. Am. Chem. Soc. 62, 2295, 1940. Themethod comprises reacting the appropriately substituted benzyl cyanidewith the appropriately substituted phenethyl bromide R and R having thesignificance hereinbefore defined, in the presence of sodamide andhydrolyzing the resulting nitrile to give the corresponding acid (XI)which is then cyclized as hereinbefore described to the u-tetralone(XII).

The following preparations and examples illustrate the best methodcontemplated by the inventor for carrying out his invention.

Preparation 1.-3-methoxychalcone A solution of 45 g. ofm-methoxyacetophenone in ml. of ethanol was added to a cooled solutionof 16 g. of sodium hydroxide in ml. of water. The mixture was thenplaced in an ice bath and 31.8 g. of benzaldehyde was added at such arate as to keep the temperature below 20 C. The mixture was stirred foran additional 30 minutes in the cold and was then stirred for 27 hoursat about 25 C. The resulting solution was extracted with ether and theextract was washed with saturated sodium chloride solution beingpercolated through anhydrous magnesium sulfate and evaporated to drynessunder reduced pressure. There was thus obtained 50.9 g. of3'-methoxychalcone in the form of an oil having a boiling point of to C.at a pressure of 4 mm. of mercury.

Using the above procedure, but replacing m-methoxyacetophenone by thefollowing compounds: methoxy-, m-pentyloxy- (prepared by etherificationof m-hydroxyacetophenone with pentyl bromide), m-hexyloxy- (preparedfrom m-hydroxyacetophenone by etherification with hexyl bromide), andm-isooctyloxyacetophenone (prepared from m-hydroxyacetophenone byetherification with isooctyl bromide), there are obtained 3'-ethoxy-,3'- pentyloxy-, 3-hexyloxy-, and 3'-isooctyloxychalcone, respectively.

Similarly, using the procedure described in Preparation 1, but replacingbenzaldehyde by the following known compounds: 2-bromobenzaldehyde,3-chlorobenzaldehyde, 2 chloro 6 fluorobenzaldehyde, 2,3dichlorobenzaldehyde, p-tolualdehyde, and 2,6-dimethylbenzaldehyde,there are obtained 2bromo-3-methoxy chalcone,3-chloro-3-methoxychalcone, 2-cl1loro-6fluoro 3'-methoxychalcone,2,3-dichloro-3'-methoxychalcone, 4- methyl-3-methoxychalcone and2,6-dimethyl-3-methoxychalcone, respectively.

Preperation 2.2-phenyl-4-(3-rnethoxyphenyl)-4- ketobutyronitrile Asolution of 27.8 g. of potassium cyanide in ml. of water was added to amixture of 50.9 g. of 3-methoxychalcone, 13.0 g. of acetic acid, and ml.of 95% ethanol over a period of 10 minutes. The temperature wasmaintained at 45 C. The turbid mixture was then stirred for 6 hours andallowed to stand overnight in the cold. The crystalline solid which hadseparated was isolated by filtration, Washed with ice-cold aqueousethanol and with water, and recrystallized from ethanol. There was thusobtained 49.22 g. of 2-phenyl-4-(3-methoxyphenyl)-4-ketobutyronitrile inthe form of a crystalline solid having a melting point of 96 to 101 C.The infrared spectrum of the compound (mineral oil mull) exhibitedmaxima at 2200, 1660, and 1580 reciprocal centimeters.

Using the above procedure, but replacing 3-methoxychalcone by 3-ethoxy-,3'-pentyloxy-, 3'-hexyloxy-, 3'isooctyloxy-, 2-bromo-3'-methoxy-,3-chloro 3 methoxy-, 2-chloro-6-fluoro-3-methoxy-, 2,3-dichloro-3'methoxy-, 4-rnethyl-3methoxy-, and 2,6-dimethyl-3'-methoxychalcone,there are obtained 2-phenyl-4-(3-ethoxyphenyl)-4- ketobutyronitrile,2-phenyl-4-(3-pentyloxyphenyl)-4-ketobutyronitrile,2-phenyl-4-(3-hexyloxyphenyl) 4 ketobutyronitrile,2-phenyl-4-(3-isooctyloxyphenyl) 4 ketobutyronitrile,2-(2-bromophenyl)4-(3 methoxyphenyl)- 4-ketobutyronitrile,2-(3-chloro-phenyl) 4 (3 methoxyphenyl) 4 ketobutyronitrile, 2 (2 chloro6 fluorophenyl -4- 3 -methoxyphenyl -4-ketobutyronitrile, 2- (2,3dich1orophenyl)4-(3 methoxyphenyl) 4 ketobutyronitrile, 2-p-tolyl-4-(3-metl1oxyphenyl) 4 ketobutyronitrile, and 2-(2,6 dimethylphenyl) 4 (3methoxyphenyl)-4-ketobutyronitrile, respectively.

Preparation 3 .-2-phenyl-4- 3-methoxyphenyl) -4- ketobutyric acid Asuspension of 49.22 g. of2-phenyl-4-(3-methoxyphenyl)-4-ketobutyronitrile in a mixture of 140 ml.of concentrated sulfuric acid and ml. of water was heated on a steambath with vigorous stirring for 4 hours. The resulting mixture wascooled and diluted with ice water. The solid which separated wasisolated by filtration and recrystallized from aqueous ethanol and thenfrom benzene. There was thus obtained 29.5 g. of 2-phenyl-4-(3-methoxyphenyl)-4-ketobutyric acid in the form of a crystalline solidhaving a melting point of to C. An analytical sample having a meltingpoint of 143 to 145 C. was obtained by recrystallization from benzene.

Analysis.Calcd. for C H O C, 71.82; H, 5.67. Found: C, 72.10; H, 5.74.

Using the above procedure, but replacing 2-phenyl-4-(3-methoxyphenyl)-4-ketobutyronitrile by the appropriately substituted2,4-diphenyl 4 ketobutyronitrile (prepared as described in Preparation2), there are obtained 2-phenyl-4-(3-eth0xyphenyl)-4-ketobutyric acid,2-phenyl-4-( 3 pentyloxyphenyl) 4 ketobutyric acid, 2phenyl-4-(3-hexyloxyphenyl) 4 ketobutyric acid, Z-phenyl-4-(3-isooctyloxyphenyl)-4-ketobutyric acid, 2(2-bromophenyl) 4 (3methoxyphenyl) 4 ketobutyric acid,2-(3-chlorophenyl)-4-(3-methoxyphenyl) 4 ketobutyric acid,2-(2-chloro-6-fluorophenyl)-4-(3 methoxyphenyl)- 4-ketobutyric acid,2-(2,3-dichlorophenyl)-4-(3-methoxyphenyl)-4-ketobutyric acid,2-p-tolyl-4-(3 methoxyphenyl-4-ketobutyric acid and2-(2,6-dimethylphenyl) 4 (3- methoxyphenyl)-4-ketobutyric acid,respectively.

Preparation 4.2-phenyl-4-(3-methoxyphenyl)-butyric acid A total of 300g. of mossy zinc was washed briefly with 2.5 N hydrochloric acid andthen with water. The metal was covered with a solution of 6.7 g. ofmercuric chloride in 500 ml. of water, and this mixture was allowed tostand for 30 minutes with occasional shaking. The liquid phase wasdecanted and the amalgamated metal was washed well with water. To theamalgamated zinc so produced was added a mixture of 29.3 g. of2-phenyl-4-(3- methoxyphenyl)-4-ketobutyric acid and 400 ml. ofhydrochloric acid. The mixture was heated cautiously to refluxtemperature and then heated under reflux for a total of 20 hours,additional portions of hydrochloric acid being added after 5 hours and10 hours of heating. The resulting mixture Was cooled and the liquid wasdecanted from the solid. The solid residue was washed well with etherand the decanted liquor was extracted with ether. The ether extract andwashings were combined and washed with water and then with saturatedsodium chloride solution before being percolated through anhydrousmagnesium sulfate. The percolate was evaporated to dryness. There wasthus obtained 26.2 g. of 2-phenyl-4-(3-methoxyphenyl)butyric acid in theform of a viscous oil which was employed without further purification inthe process of Preparation 5. The infrared spectrum of the compound(mineral oil mull) exhibited a maximum at 1705 reciprocal centimeters.

Using the above procedure, but replacing the 2-phenyl-4-(3-methoxyphenyl) 4 ketobutyric acid by the appropriately substituted2,4-diphenyl-4-ketobutyric acid (prepared as described in Preparation3), there are obtained 2-phenyl-4-(3-ethoxyphenyl), 2-phenyl-4-(3pentyloxyphenyl)-, 2-phenyl-4-(3-hexyloxyphenyl)-, 2-phenyl-4-(3-isooctyloxyphenyl)-, 2-(2-bromophenyl)-4-(3 methoxyphenyl)-,2-(3-chlorophenyl) 4 (3 methoxyphenyl)-, 2-(2-chloro-6-fluorophenyl) 4(3 methoxyphenyl), 2-(2,3-dichlorophenyl)-4-(3-methoxyphenyl)-, 2-tolyl- 4-(3-methoxyphenyl)-, and 2-(2,6-dimethylphenyl)-4-(3methoxyphenyl)-butyric acids, respectively.

Preparation 5.--2-phenyl-6-methoxy-1,2,3,4- tetrahydrol-naphthalenone Atotal of ml. of liquid hydrogen fluoride was added to 26.2 g. of2-phenyl-4-(3-methoxyphenyl)butyric acid with cooling and swirling. Theresulting mixture was allowed to stand at room temperature for 3 days.The residue was dissolved in methylene chloride and the solution waspoured into excess concentrated aqueous potassium carbonate solution.The organic layer was separated, washed with water and saturated sodiumchloride solution, and then evaporated to dryness. The residue wasdissolved in 2 l. of mixed hexanes (Skellysolve B) containing 7.5% byvolume of acetone and the solution was passed through a column ofmagnesium silicate (Florisil) prewashed with the same solvent mixture.The eluate was evaporated to dryness and the residue (17.0 g.) wasrecrystallized twice from cyclohexane. There was thus obtained 13.38 g.of 2-phenyl-6-trnethoxy-1,2,3,4-tetrahydrol-naphthalenone in the form ofa crystalline solid having a melting point of 113 to 116 C.

Analysis.-Calcd. for C H O C, 80.92; H, 6.39. Found: C, 81.08; H, 6.35.

Using the above procedure, but replacing 2-phenyl-4-(3-methoxyphenyl)butyric acid by the appropriately substituted2,4-diphenylbutyric acid (prepared as described in Preparation 4), thereare obtained 2-phenyl-6-ethoxy-. 2-phenyl-6-pentyloxy-, 2-phenyl 6hexyloxy-, 2-phenyl 6-is0octyloxy-, 2-(2-bromophenyl) 6 methoxy-, 2-(3-chlorophenyl) -6-methoxy-, 2- 2-chloro-6-fluorophenyl) -6- methoxy-,2-(2,3-dichlorophenyl)-6methoxy-, 2-p-tolyl-6- methoxy-, and2-(2,6-dimethylphenyl)-6-methoxy-1,2,3,4- tetrahydro-l-naphthalenones,respectively.

Preparation 6.1,2-diphenyl-6-methoxy-3,4- dihydronaphthalene A solutionof 5.04 g. (0.02 mole) of 2 phenyl 6-methoxy-1,2,3,4-tetrahydro-1-naphthalen0ne in 75 ml. of tetrahydrofuranwas added to an ice-cooled solution of the Grignard reagent preparedfrom 31.4 g. (21 ml.) of bromobenzene and 4.90 g. of magnesium in 200ml. of

ether. The resulting mixture was allowed to stand at room temperature(approximately 20 C.) for 16 hours before being decomposed by thecareful addition of Water. The mixture so obtained was filtered and theorganic filtrate was washed with water and with saturated sodiumchloride solution before being dried over anhydrous sodium sulfate. Thedried solution was filtered and the filtrate was evaporated to dryness.The residual gum was dissolved in methylene chloride and chromatographedtwice over magnesium silicate (Florisil). The columns were eluted withpetroleum ether containing increasing proportions of acetone an thosefractions which, on the basis of paper chromatographic analysis, werefound to contain the desired product were combined and evaporated todryness. The fractions so obtained from the second chromatography wererecrystallized from aqueous methanol. There was thus obtained 2.5 g. of1,2-diphenyl-6-methoxy-1,2,3,4- tetrahydro-l-naphthol in the form of acrystalline solid having a melting point of 112 to 116 C. An analyticalsample having a melting point of 113 to 116 C. was obtained by furtherrecrystallization from petroleum ether.

Analysis.Calcd. for C H O C, 82.98; H, 6.96. Found: C, 83.60; H, 6.93.

A solution of 1 g. of 1,2-diphenyl-6-methoxy-1,2,3,4-tetrahydro-l-naphthol (prepared as described above) and 0.1 g. ofp-toluenesulfonic acid in 100 ml. of toluene was heated for hours atreflux under a Dean-Starke water trap. The solvent was then distilledfrom the reaction mixture and the residue was dissolved in ether. Theethereal solution was washed with saturated aqueous sodium bicarbonatesolution, then with water, and finally with saturated sodium chloridesolution. The washed ether solution was evaporated to dryness and theresidue was recrystallized twice from Skellysolve B. There was thusobtained 0.52 g. of l,2-diphenyl-6-methoxy-3,4-dihydronaphthalene in theform of a crystalline solid having a melting point of 90 to 92 C.

Analysis.Calcd. for C H O: C, 88.42; H, 6.45. Found: C, 87.99; H, 6.78.

Using the above procedure but replacing 2-phenyl-6-methoxy-1,2,3,4-tetrahydro-l-naphthalenone by 2-phenyl-6-ethoxy-,

2-phenyl-6-pentyloxy-,

2-phenyl-6-hexyloxy-,

2-phenyl-6-isoo-ctyloxy-,

2- (Z-bromophenyl -6-methoxy-,

2- 3-chlorophenyl -6-tmethoxy-,

2- (2-chloro-6-fluorophenyl -6-methoxy-,

2- (2,3-dichlorophenyl) -6-methoxy-,

2- (p-tolyl) -6-methoxy-, and

2- (2,6-dimethylphenyl) -6-methoxy-1,2,3,4-

tetrahydro-l-naphthalenone,

there are obtained 1,2-diphenyl-6-ethoxy-, 1,2-diphenyl- 6-pentyloxy-,1,2-diphenyl-6-hexyloxy-, l,Z-diphenyl-6-isooctyloxy-, 1-phenyl-2-2-bromophenyl) -6-methoxy-, 1-pheny1-2- 3-chlorophenyl) -6-methoxy-,1-pheny1-2- 2-chloro-6-fiuorophenyl) -6-meth0xy-, 1-phenyl-2-2,3-dichlorophenyl) -6-methoxy-, 1-phenyl-2- (p-tolyl -6-methoxy-, and1-phenyl-2- (2,6-dimethylphenyl) -6-rnethoxy- 3,4-dihydronaphthalene,respectively.

Preparation 7.1-(p-hydroxyphenyl)-2-phenyl-6-methoxy-3,4-dihydronaphthalene A solution of 5.83 g. of2-phenyl-6-methoxy-1,2,3,4- tetrahydro-l-naphthalen-one in 75 ml. oftetrahydrofuran was added to a tetrahydrofuran solution containing0.0247 mole of the Grignard reagent prepared from p-bromophenyltetrahydropyranyl ether (Parham et al., J. Am. Chem. Soc. 70, 4187,1948). The resulting mixture was heated under reflux for 16 hours. Atthe end of this time the mixture was cooled and 10 ml. of water wasadded. The resulting mixture was filtered and the filtrate was dilutedwith ether. The organic layer was separated, washed well with water, anddried over anhydrous sodium sulfate. The dried solution was filtered andthe filtrate was evaporated to dryness under reduced pressure. Theresidue was dissolved in ml. of tetrahydrofuran and again treated withthe Grignard reagent as described above. The reaction mixture from thesecond Grignard reaction was worked up exactly as described for thefirst reaction mixture. The gum so obtained was dissolved in 200 ml. ofbenzene containing 200 mg. of p-toluenesulfonic acid and the mixture washeated under reflux under a Dean- Starke water trap until no furtherwater was collected in the trap. The solvent was removed from thesolution by distillation under reduced pressure and the residue wasdissolved in a mixture of 200 ml. of acetone and 70 ml. of 0.5 Nhydrochloric acid. The solution so obtained was allowed to stand for 2hours at room temperature (about 25 C.) and then extracted with ether.The organic layer was separated and extracted with 5% aqueous potassiumhydroxide solution. The aqueous alkaline extract was acidified by theaddition of hydrochloric acid and the solid which separated was isolatedby filtration and dried. The material so obtained was dissolved inmethylene chloride and chromatographed on a column of Florisil(magnesium silicate). The column was eluted with Skellysolve Bcontaining increasing proportions of acetone and those fractions which,on the basis of infrared and papergram analysis, were found to containthe desired compound were combined and evaporated to dryness. Theresidue was recrystallized twice from cyclohexane. There was thusobtained 0.71 g. of l-(phydroxyphenyl) 2phenyl-6-methoxy-3,4-dihydronaphthalene in the form of a crystallinesolid having a melting point of to 131.5 C.

Analysis.Calcd. for C H O C, 84.12; H, 6.14. Found: C, 83.64; H, 5.96.

Using the procedure described above but replacing 2-phenyl-6-methoxy-1,2,3,4-tetrahydro-1-naphthalenone by2-pheny1-6-ethoxy-, 2-phenyl-6-pentyloxy-, 2-phenyl-6-hexyloxy-,2-phenyl-6-isooctyloxy-, 2-(2-bromophenyl)-6-methoxy-,2-(3-chlorophenyl)-6-methoxy-, 2-(2-chloro-6-fluorophenyl)-6-methoxy-,2-(2,3-dichlorophenyl)-6-methoxy-, 2-(p-tolyl)-6-methoxy-, and2-(2,6-dimethylphenyl)-6-methoxyl,2,3,4-tetrahydro-1- naphthalenone,

there are obtained 1-(p-hydroXyphenyl)-2-phenyl-6-ethoxy-,1-(p-hydroxyphenyl)-2-phenyl-6-pentyloxy-,1-(p-hydroxyphenyl)-2-phenyl-6-hexyloxy-,1-(p-hydroxyphenyl)-2-phenyl-6-isooctyloxy-,1-(p-hydroxyphenyl)-2-(2-bromophenyl)-6-methoxy-,l-(p-hydroxyphenyD-Z-(3-chl-orophenyl)-6-methoxy-,1-(p-hydroxyphenyl)-2-(2-chloro-6-fluorophenyl)-6- methoxy-,l-(p-hydroxyphenyl)-2-(2,3-dichlorophenyl)-6-methoxy-,1-(p-hydroxyphenyl)-2-(p-tolyl)-6-methoxy-, and1-(p-hydroxyphenyl)-2-(2,6-dimethylphenyl)-6-methoxy-3,4-dihy-dronaphthalene, respectively.

The corresponding l-(o-hydroxyphenyD- and l-(m-hydroxyphenyl-2-substituted-6-substituted-3,4-dihydronaphthalenes are obtained byemploying o-bromophenyl tetrahydropyranyl ether and m-bromophenyltetrahydropyranyl ether, respectively, in place of p-bromophenyltetrahydropyranyl ether in the procedure of Preparation 7.

Preparation 8.l-(p-fiuorophenyl)-2-phenyl-6-methoxy-3,4-dihydronaphthalene Using the procedure described in Preparation 6,but replacing bromobenzene by p-bromofiuorobenzene, there was obtained1-(p-fluorophenyl)-2-phenyl-6-methoxy-3,4- dihydronaphth-alene in theform of a crystalline solid having a melting point of 99 to 101 C.

Similarly other 1-(halophenyl)-2-phenyl-6-alkoxy-3,4-dihydronaphthalenesare obtained by reacting the appropriate halophenylmagnesium halide withthe appropriate 2- phenyl-6-alkoxy-1,2,3,4-tetrahydro-l-naphthalenoneusing the procedure described in Preparation 6.

Preparation 9.1-(p-tolyl)-2-phenyl-6-methoxy 3,4-dihydronaphthaleneExample 1.-l ,2-dipheny1-6-methoxy-1,2,3,4- tetrahydronaphthalene Asolution of 0.63 g. of 1,2-diphenyl-6-methoxy-3,4- I

dihydronaphthalene in 20 ml. of tetrahydrofuran and 1 ml. of tert. butylalcohol was added to 100 ml. of ammonia redistilled from lithium. Tothis there was added 28 mg. of lithium wire; the color faded veryquickly. After 5 to 10 minutes an additional 28 mg. of lithium wereadded. The blue color this time prevailed for 20 minutes. After theaddition of 1 g. of solid ammonium chloride, the mixture was taken todryness under a stream of nitrogen. The residue was then washed withether and methylene chloride. The solid which remained when the extractswere taken to dryness was recrystallized from ethanol. There was thusobtained 0.53 g. of 1,2-diphenyl-6-methoxy-1,2,3,4-tetrahydronaphthalene having a melting point of 160 to162 C.

One further crystallization from the same solvent gave an analyticalsample, MP. 166 to 168 C.

AnalysisCalcd. for C H O: C, 87.86; H, 7.05. Found: C, 87.30; H, 7.13.

Example 2.1 (p-hydroxyphenyl)-2-phenyl-6-methoxy-1,2,3,4-tetrahydronaphthalene One gram of 1 (p hydroxyphenyl)2-phenyl-6-methoxy-3,4-dihydronaphthalene was reduced by means of 84 mg.of lithium in exactly the same manner as described in Example 1. Thegummy solid which remained when the solvents had been removed from thereaction mixture was suspended in water and the suspension was acidifiedwith acetic acid. The solid was collected on a filter and recrystallizedtwice from methanol to yield 0.40 g. of l (phydroxyphenyl)-2-pheny1-6-methoxy-1,2,3,4-tetrahydronaphthalene, havinga melting point of 188 to 190 C.

AnalysisCalcd. for 0 11 0 C, 83.60; H, 6.71. Found: C, 83.45; H, 6.89.

Example 1 1.-1- (p-methoxyphenyl) -2-phenyl-6-methoxy-1,2,3,4-tetrahydronaphthalene Using the procedure described in Example6, but replacing 3-chloro-1,2-propanediol by methyl iodide and reducingthe reaction time to 2 hours, there is obtained 1(p-methoxyphenyl)-2-phenyl-6-methoxy-1,2,3,4-tetrahydronaphthalene.

Example 12. l-(p-tolyl)-2-phenyl-6-methoxy-1,2,3,4-tetrahydronaphthalene Using the procedure described in Example 1, butreplacing 1,2-diphenyl-3,4-dihydronaphthalene by 1-(ptolyl)-2-pheny1-6-methoxy-3,4-dihydronaphthalene, there is obtained 1-(p-tolyl) -2-phenyl-6-meth0xy-1,2,3 ,4-tetrahydronaphthalene.

Similarly, using the procedure described in Example 1, but replacingl,2-diphenyl-3,4-dihydronaphthalene by lp-hydroxyphenyl)-2-phenyl-6-ethoxy-,

1- (p-hydroxyphenyl) -2-phenyl-6-pentyloxy-,

1- (p-hydroxyphenyl) -2-phenyl-6-hexyloxy-,

l- (p-hydroxyphenyl) -2-phenyl-6-isooctyloxy-,

1- p-hydroxyphenyl) -2- (2-bromophenyl) -6-rnethoxy-,

1- (p-hydroxyphenyl -2- 3-chlorophenyl) -6-methoxy-,

1- p-hydroxyphenyl) -2- 2-chloro-6-fluorophenyl -6- methoxy-,

1- (p-hydroxphenyl) -2- (2,3 -dichlorophenyl) -6-methoxy-,

1- p-hydroxyphenyl) -2- (p-tolyl) -6-methoxy-,

lp-hydroxyphenyl -2- (2,6-dimethylphenyl) -6-meth1,2-diphenyl-6-ethoxy-,

1,2-diphenyl-6-pentyloxy-,

1,2-diphenyl-6-hexyloxy-,

1,2-diphenyl-6-isoctyloxy-,

1-phenyl-2- 2-bromophenyl) -6-methoxy-,

1-phenyl-2-( 3 -chlorophenyl -6-methoxy-,

1-pheny1-2-(2-chloro-6-fluorophenyl)-6-methoxy-,

1-phenyl-2- (p-tolyl) -6-methoxy-,

l-phenyl-2-(2,6-dimethylphenyl)-6-methoxy-, and

1- (p-fluorophenyl) -2-phenyl-6-methoxy-3,4-dihydronaphthalenes,

there are obtainedthe corresponding 1,2,3,4-tetrahydronaphthalenes.

The l-(hydroxyphenyl)-1,2,3,4-tetrahydronaphthalenes so obtained areconverted to the corresponding l-(tertiaryaminoalkoxyphenyl)-,1-(alkoxyphenyl)-, l-(carbalkoxyalkoxyphenyl)-,l-(carboxyalkoxyphenyl)-, l-(epoxyalkoxyphenyl) 1[(Z-amino-l-hydroxyethyl) alkoxyphenyl]-, l-{ [5-(2-oxooxazolidinyl)alkoxyphenyl}-, 1- {[5 (2 thioxooxazolidinyl)]alkoxyphenyl}-, and1-(dihydroxyalkoxyphenyl)-derivatives thereof using the procedures setforth in Examples 3 through 11, above.

Example 13 1,2-diphenyl-6-methoxy-1,2,3,4,5,8- hexahydronaphthalene Asolution of 0.31 g. of 1,2-diphenyl 6-methoxy-1,2,3,4-tetrahydronaphthalene in 10 ml. of tetrahydrofuran and 1 ml. oftert.butyl alcohol was added to 50 m1. of liquid ammonia redistilledfrom lithium. Lithium wire (0.07 g.) was added in 7 equal portions tothe mixture at 5-minute intervals. The resulting mixture was stirred for30 minutes before 3 ml. of tert.butyl alcohol was added. Following anadditional 25 minutes stirring, there was added 0.3 g. of ammoniumchloride. The solvent was evaporated from the mixture under a stream ofnitrogen and the residue was treated with water. The solid was collectedon a filter and recrystallized from ligroin to afford1,2-diphenyl-6-methoxy-l,2,3,4,5,8-hexahydronaphthalene having a meltingpoint of 132 to 134 C.

Analysis.Calcd. for C H O: C, 87.30; H, 7.65. Found: C, 87.02; H, 7.90.

Example 14.-1-(p-hydroxyphenyl)-2-phenyl-6-methoxy-1,2,3,4,5,8-hexahydronaphthalene Using the procedure described inExample 13, 0.66 g.

of 1-(p-hydroxyphenyl)-2-phenyl 6-methoxy 1,2,3,4-

tetrahydronaphthalene was reduced with 154 mg. of

15 lithium. The reaction mixture was worked up as in Example 13 and theproduct was recrystallized from aqueous methanol. There was obtained0.55 g. of l-(phydroxyphenyl) 2-phenyl 6-methoxy 1,2,3,4,5,8-hexahydronapthalene having a melting point of 184.5 to 187.5 C.

An analytical sample prepared by further recrystallization from the samesolvent melted at 183 to 185 C.

Analysis.Calcd. for C H O C, 83.10; H, 7.28. Found: C, 83.07; H, 7.40.

Using the procedure described in Example 13, but replacing1,2-diphenyl-6-methoxy 1,2,3,4-tetrahydronaphthalene by theappropriately substituted 1,2-diphenyl- 6-alkoxy1,2,3,4-tetrahydronaphthalene is productive of the corresponding1,2,3,4,5,8-hexahydronaphthalene. Representative of the latter compoundsso prepared are 1- (p-hydroxyphenyl) -2-phenyl-6-ethoxy-,

1- p-hydroXy-p-henyl -2-phenyl- 6-pentyloxy-,

1- (p-hydroxyphenyl) -2-phenyl-6-hexyloXy-,

1- (p-hy-droxyphenyl) -2-phenyl-6-isooctyloxy-,

1- (p-hydroxyphenyl) -2- (2-bromophenyl) -6-m thoxy-,

1- (p-hydroxyphenyl) -2- 3-chlorophenyl) -6-methoxy-,

1- (p-hydroxyphenyl) -2- (2-chloro-6-fiuorophenyl) -6- methoxy-,

1- (p-hydroxyphenyl) -2- 2,3-dichlorophenyl) -6-methoxy-,

1- p-hydroxyphenyl -2- (p-tolyl) -6-methoxy-,

1- p-hydroxyphenyl -2- (2,6-dimethylphenyl) -6-meth0xy-,

1,2-diphenyl-6-ethhoxy-,

1,Z-diphenyl-6-pentyloxy-,

1,2-diphenyl-6-hexyloxy-,

1,Z-diphenyl-6-isooctyloxy,

l-phenyl-2- 2-b romophenyl -6-meth0xy-,

1-phenyl-2- 3-chlorophenyl) -6-methoxy-,

l-phenyl-Z- 2-chloro-6-fluorophenyl) -6-methoxy-,

1-phenyl-2- (p-tolyl) -6-methoxy,

1-phenyl-2-(2,6-dimethylph nyl)-6- Y- and1-(p-fiuorophenyl)-2-phenyl-6-methoxy-1,2,3,4,5,8-

hexahydronaphthalene.

The above compounds which contain a l-(hydroxyphenyl) substituent can beetherified according to the procedures set forth in Examples 3 through11 to produce the corresponding 1-(alk0xyphenyl)-,l-(tertiaryaminoalkoxyphenyl)-, 1 (carbalkoxyalkoxyphenyl)-, 1(carboxyalkoXyphenyl)-, 1 (epoXyalkoxyphenyl)-, 1 [(2 amino 1hydroxyethyl)alkoxyphenyl] ,1 (2 oxooxazolidinyl)]alkoxyphenyl}, 1 {[5(2 thioxooxazolidinyl)]alkoxyphenyl}-, and 1 (dihydroxyalkoxyphenyD-derivatives thereof.

Example 15 .--5,6-diphenyl-3,4,5, 6,7,8-hexahydro 2 1H) -naphtha1enone Asuspension of 2.0 g. of 1,2-diphenyl-6-methoxy-1,2,3,4,5,8-hexahydronaphthalene in 400 ml. of methanol and ml. of 2.5 Nhydrochloric acid was stirred for 20 minutes in an ice bath and 1 hourat room temperature (about C.). The now homogeneous solution wasneutralized with saturated aqueous sodium bicarbonate solution and thebulk of the solvent was removed on a rotary evaporator. Ether was addedto the residue and the organic layer was washed with water and saturatedsodium chloride solution before being evaporated to dryness. Theresidual gum was recrystallized 3 times from a small amount of ligrointo give 0.82 g. of5,6-diphenyl-3,4,5,6,7,8-hexahydro-2(1H)-naphthalenone having a meltingpoint of 124 to 129 C.

An analytical sample, melting point 128 to 132 C., was obtained byrecrystallization from ligroin of the product from another run.

Analysis.-Calcd. for C H O: C, 87.37; H, 7.33. Found: C, 87.77; H, 7.42.

1 6 Example 16.5- (p-hydroxyphenyl) -6-phenyl-3,4, 5, 6,7, 8-

hexahydro-2( 1H -naphthalenenone A suspension of 1.65 g. ofl-(p-hydroxyphenyl) 2- phenyl 6-methoxy 1,2,3,4,5,8-hexahydronaphthalenein 83 ml. of methanol containing 3.3 ml. of 1 M methanolic oxalic acidwas stirred at room temperature (about 25 C.) until the material was allin solution (40 minutes). The solution was then taken to dryness atreduced pressure and the residue was dissolved in a mixture of ether andmethylene chloride. This solution was washed in turn with water, aqueoussodium bicarbonate solution, and saturated sodium chloride solution. Theresidue which remained when the solvent was removed from the organiclayer was recrystallized from methanol. There was obtained a first cropof 0.53 g. of 5-(p-hydroxyphenyl)-6- phenyl 3,4,5,6,7,8 hexahydro2(lH)-naphthalenone having a melting point of 209 to 216 C.; the secondcrop of material was recrystallized from aqueous methanol to give anadditional 0.90 g. of the same compound having a melting point of 213 to216 C.

The analytical sample, obtained by recrystallization of the first cropfrom methanol, melted at 215 to 224 C.

Analysis.-Calcd. for C H O C, 82.98; H, 6.96. Found: C, 82.72; H, 7.28.

Using the procedure described in Example 15, but replacing 1,2-diphenyl6-methoxy l,2,3,4,5,8-hexahydronaphthalene by the 1,2,3,4,5,8hexahydronaphthalenes disclosed immediately after Example 14 there areproduced the following 3,4,5,6,7,8-hexahydro-2(1H)naphthalenones:

5 p-hydroxy phenyl -6-phenyl-,

5 (p-hydroxyphenyl) -6- 2-bromophenyl 5 p-hydroxyphenyl) -6-3-chlorophenyl) 5- (p-hydroxyphenyl -6- 2-chloro-6-fluorophenyl) 5p-hydroxyphenyl -6- 2,3-dichlorophenyl) 5- (p-hydroxyphenyl-6- (p-tolyl)5 p-hydroxyphenyl) -6- (2,6-dimethylphenyl 5 ,6.-diphenyl-,

5 -phenyl-6- 2-bromophenyl) 5-phenyl-6- 3-chlorophenyl) 5-phenyl-6-(2-chloro-6-fiuorophenyl) 5-phenyl-6- (p-tolyl) 5 -phenyl-6-2,6-dimethylphenyl) and 5- (p-fluorophenyl) 6-phenyl-3,4,5,6,7,8-hexahydro- 2 1H) -naphthalenone.

The above compounds which contain a S-(hydroxyphenyl) substituent can beetherified according to the procedures set forth in Examples 3 through11 to produce the corresponding 5- (alkoxyphenyl) 5-(tertiaryaminoalkoxyphenyl) 5- (carbalkoxyalkoxyphenyl) 5carboxyalkoxyphenyl 5- (expoxy alkoxyphenyl) 5-[ (Z-aminol-hydroxyethyl)alkoxyphenyl] 5-{ [5- 2-thioxooxazolidinyl) ]alkoxyphenyl}-, and 5-(dihydroxalkoxyphenyl -derivatives thereof.

Similarly, using the above procedure, but replacing hydrochloric acid byother acids such as sulfuric acid, hydrobromic acid, phosphoric acid,acetic acid, methanesulfonic acid, and the like, there are obtained thecorresponding quaternary ammonium salts.

In like manner, using the above procedure, the anion of any of thequaternary ammonium salts of the invention can be exchanged by any otherdesired anion by forming the corresponding quaternary ammonium hydroxideand reacting the latter with the appropriate acid.

3,497,557 17 18 I claim: 2. A compound having the formula: 1. A compoundhaving the formula:

1O w W'Q wherein R and R are hydrogen.

r m o: l

\/ No references cited.

15 ALEX MAZEL, Primary Examiner J. TOVAR, A t t Examin wherein R isselected from the class consisting of hydro- $818 an er gen, lower-alkylhaving from 1 to 8 carbon atoms, inus CL clusive, and halogen; and R ishydrogen. 424 331 Patent No. 3, 97,557 Dated February 26, 1971Inventor(s) Daniel Lednicer It is certified that error appears in theabove-identified patent and thatsaid Letters Patent are hereby correctedas shown below:

Column 1, l ines 59 and 60, for 'gen, and lower-alkyl and halogen; andwherein R is selected from the lower-a l koxy subst itu ted by" readgen, lower-al kyl and halogen; and wherein R is selected from the classconsisting of hydrogen, hydroxy, halogen and lower-alkyl Column 2, lines 1 through 21 should be deleted.

Column 3, Formula I the specific structure should be:

Column 5, Formula IX should be:

NCT QC R0 ll Column 8, l ine 52, for solut ion being read solut ionbefore be ing Column 14, l ine 68, for "C H3 O" read C H 0 (continued)FORM PO-I D (10-69) USCOMM-DC oos'ra-Pen Q 1L5 GDVIRNMENT PRINTINGOFFICE "I! 0-365-334 Page -2- UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION Patent No. 3 97,557 Dated February 26, 1971 Inventor(s)Daniel Lednicer It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 15, l ine 9, for "C Ha4O" read C H 4O Column 16, l lnes 65through 75 should be deleted.

Signed and sealed this 8th day of June 1971.

(SEAL) Attest:

EDWARD M.FIETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting OfficerCommissioner of Patents FORM PO-I (10-69) uscoMM-oc 60376-P59 if ILS.GOVIRNMENT PRINTING OFHC! 1,! O-JlG-JJI

